Cancer of the prostate is the most commonly diagnosed cancer in men and is the second most common cause of cancer death (Carter and Coffey, Prostate 16:39-48, 1990; Armbruster et al., Clinical Chemistry 39:181, 1993). If detected at an early stage, prostate cancer is potentially curable. However, a majority of cases are diagnosed at later stages when metastasis of the primary tumor has already occurred (Wang et al., Meth. Cancer Res. 19:179, 1982). Even early diagnosis is problematic because not all individuals who test positive in these screens develop cancer.
Prostate specific antigen (PSA) is a 240 amino acid member of the glandular kallikrein gene family. (Wang et al., 1982, supra; Wang et al., Invest. Urology, 17:159, 1979; Bilhartz et al., Urology, 38:95, 1991). PSA is a serine protease, produced by normal prostatic tissue, and secreted exclusively by the epithelial cells lining prostatic acini and ducts (Wang et al., 1982, supra; Wang et al., 1979, supra; Lilja et al., World J. Urol., 11:188-191, 1993). Prostate specific antigen can be detected at low levels in the sera of healthy males without clinical evidence of prostate cancer. However, during neoplastic states, circulating levels of this antigen increase dramatically, correlating with the clinical stage of the disease (Schellhammer et al., Urologic Clinics of North America 20:597, 1993; Huang et al., Prostate 23:201, 1993). Prostate specific antigen is now the most widely used marker for prostate cancer. However, there clearly is a need to identify additional antigens to aid in the diagnosis of prostate cancer, and for use as therapeutic agents.
Present treatment for prostate cancer includes radical prostatectomy, radiation therapy, or hormonal therapy. With surgical intervention, complete eradication of the tumor is not always achieved and the observed re-occurrence of the cancer (12-68%) is dependent upon the initial clinical tumor stage (Zietman et al., Cancer 71:959, 1993). Thus, alternative methods of treatment including prophylaxis or prevention are desirable.
Immunotherapy is a potent new weapon against cancer. Immunotherapy involves evoking an immune response against cancer cells based on their production of target antigens. Immunotherapy based on cell-mediated immune responses involves generating a cell-mediated response to cells that produce particular antigenic determinants, while immunotherapy based on humoral immune responses involves generating specific antibodies to cells that produce particular antigenic determinants.
Cancer cells produce various proteins that can become the target of immunotherapy; antigenic determinants normally present on a specific cell type can also be immunogenic. For example, Rosenberg et al. have shown that tumor infiltrating lymphocytes target and recognize antigenic determinants of the protein MART-1, produced by both normal melanocytes and malignant melanoma cells. Furthermore, active or passive immunotherapy directed against MART-1 or peptides of it that bind to MHC Class I molecules (epitopes of HLA A2, in particular) results in the destruction of melanoma cells as well as normal cells that produce MART-1 (Kawakami et al., J. Immunol. 21:237, 1998). The tissue specificity of PSA has made it a potential target antigen for active specific immunotherapy (Armbruster et al., Clin. Chemistry 39:181, 1993; Brawer et al., Cancer Journal Clinic 39:361, 1989), especially in patients who have undergone a radical prostatectomy in which the only PSA expressing tissue in the body should be in metastatic deposits.
Recent studies using in-vitro immunization have shown the generation of CD4 and CD8 cells specific for PSA (Peace et al., Cancer Vaccines: Structural Basis for Vaccine Development (Abstract), 1994; Correale et al., 9th International Congress of Immunology (Abstract), 1995), and methods for inducing an immune response against PSA include the use of viral vectors incorporating DNA encoding PSA (e.g. see U.S. Pat. No. 6,165,460; Hodge et al., Cancer 63:231, 1995). Discovery of additional antigens expressed by the prostate gland can similarly be used to design immunotherapy methods for prostate cancer.